Substituted tetraarylporphyrins, particularly monofunctionalized porphyrins, are known to be useful in the area of facilitated transport of oxygen as demonstrated by Hasegawa et al. in Eur. Polymer J. 1978, 14, 123-127. Such compounds are also known to serve as valuable precursors to tumor imaging agents and therapeutics (radiopharmaceuticals) as taught by Schmitt et al. in Australian Patent Application 3045/83 to F. Hoffman-LaRoche & Co., 1983. Monofunctionalized porphyrins have also been utilized in the cyclodextrin catalysis area (see Gonzalez et al., Can. J. Chem. 1985, 63, 602).
Known methods for synthesis of nitro-substituted tetraarylporphyrins provide low yields of desired product and require difficult isolation procedures. For example, Rothmund condensations in which two different aromatic aldehydes are condensed with pyrrole result in yields less than 3% of desired product (Hasegawa et al., Eur. Polymer J. 1978, 14, 123-127). The Hasegawa et al. process can be summarized as follows ##STR1## In the Hasegawa et al. process five different porphyrins were produced in the crossed condensation of benzaldehyde and p-nitrobenzaldehyde with pyrrole. The isolation of the desired product (compound of formula I) required repetitive silica gel chromatography. The low yields and purification problems have been noted by others who have employed crossed-condensation methodologies in the synthesis of functionalized porphyrins (see Gonzalez et al. Can. J. Chem. 1985, 63, 602; Little et al. J. Heterocycle. Chem. 1975, 12, 343; and Schmidt et al. Australian Patent Application 3045/83 to F. Hoffman-LaRoche & Co., 1983).
The above-noted problems have prompted others to consider direct peripheral functionalization of symmetrical tetraarylporphyrins. The electrophillic addition of sulfuric acid to the phenyl ring of tetraphenylporphyrin is one of the few examples in the prior art of aryl group modification without concomitant attack on the macrocycle ring (see Winkelman et al., Cancer Research 1967, 27, 2060; Winkelman, Cancer Research 1961, 22, 589; Robinson et al., J. Nucl. Med. 1986, 27, 239; Busby et al., Can. J. Chem. 1975, 53, 1554; and Srivastava et al., J. Org. Chem. 1973, 38, 2103). However, such processes result in substitution at all four phenyl groups during the course of the reaction and stepwise sulfonation is difficult to control.
It is taught in the art that direct nitration of aryl moieties requires the presence of a substantial amount of sulfuric acid as a catalyst in order for nitration to occur (see, for example, Morrison and Boyd, Organic Chemistry, 3rd ed., 1973, Allyn and Bacon, Inc., Boston, pp. 337-371). With respect to direct nitration of a tetraarylporphyrin, substitution at the aryl position has heretofore been unknown. When such direct nitration had been attempted, products substituted at either the beta position or the meso position have been produced. The above-noted ring positions are illustrated below for tetraphenylporphyrin ##STR2##
It has been demonstrated that the sole route of nitro substitution for prior art processes occurs at the beta position of the macrocycle ring under a variety of free radical oxidation conditions (see Baldwin et al., Tetrahedron, 1982, 38, 685; Crossley et al., J. Chem. Soc. Chem. Commun., 1984, 1535; and Evans et al., J. Chem. Soc.: Perkin Trans. I, 1978, 768). In addition, Johnson et al. (Chemistry and Industry, 1975, 351) have reported that sulfuric acid catalyzed nitration of tetraphenylporphyrin has led to tetraphenylporphyrin substituted with a nitro moiety at the beta position in mixture with two meso-substituted products having the following formulae: ##STR3##
There are no known processes in the prior art for direct mono-nitration and/or stepwise nitration of tetraarylporphyrins at the peripheral aryl position(s). The present invention provides for such a process.